Antibiotics – back to basics
Petra Schelstraete
Kinderinfectieziekten UZ Gent
LOK groep 01/12/2012
To be discussed
• History
• Basic principles of AB therapy and AB/host/infective organism interaction
• AB classes + use
Antibiotics: Introduction
• Antibiotics = a natural substance produced by a micro-organism to kill another
• Anti-infectives/Anti-microbrial = any agent (natural or synthetic) that kills pathogens (microbes)
• Antibiotics exploit the differences between bacterial and human cells: drug is more toxic to the infecting organism than to the host
Antibiotics: History
• Alexander Fleming observed antibiosis against bacteria by a fungus of the genus Penicillium in 1928
• Florey and Chain succeeded in purifying the first penicillin in 1942
• Chain, Florey and Fleming: Nobel Prize in Medicine in 1945
Antibiotics: History
Bacteria
Gram-positieve kokken
Staphylococcus aureus
Staphylococcus epidermidis en andere coagulase-negatieve stafylokokken
Staphylococcus saprophyticus
Streptococcus pyogenes (groep A, β-hemolytisch) en groepen C en G
Streptococcus agalactiae (groep B, β-hemolytisch)
Streptococcus viridans
Streptococcus bovis groep D
Peptostreptococcus (anaërobe streptokok)
Streptococcus pneumoniae (pneumokok)
Enterococcus species groep D
Gram-positieve staafjes
Aërobe Bacillus anthracis
Corynebacterium diphtheriae
Listeria monocytogenes
Anaërobe Clostridium difficile (pseudomembraneuze colitis)
Clostridium perfringens (welchii)
Clostridium tetani
Gram-negatieve kokken
Neisseria gonorrhoeae (gonokok)
Neisseria meningitidis (meningokok)
Moraxella catarrhalis
Gram-negatieve staafjes
Aërobe
Enterobacteriën
Citrobacter species
Enterobacter species
Escherichia coli
Klebsiella pneumoniaeProteus mirabilis (indol-negatief)Providencia rettgeri, Morganella morganii, Proteus vulgaris en Providencia stuartii
Salmonella Typhi en andere salmonellae
Serratia species
Shigella species
Yersinia enterocolitica
Andere Gram-negatieve staafjes
Acinetobacter speciesBordetella pertussis (kinkhoest)Brucella (brucellose)Calymmatobacterium granulomatisFrancisella tularensis (tularemie)Gardnerella vaginalisHaemophilus ducreyi (ulcus molle)Haemophilus influenzaeLegionella pneumophilaPseudomonas aeruginosaVibrio cholerae
Anaërobe
Bacteroides fragilis en non-fragilis
Fusobacteriën
Prevotella
Porphyromonas
AB effect: micro-organism and host
• Micro-organism: – Bactericidal/bacteriostatic effect
• Host : side effects – Diarrhea, dental staining
– Toxic/related to dose: eg AG and nefrotoxicity
– Toxic/not related to dose: eg hepatitis
– Allergic: eg anaphylaxis in penicillin allergic patients
– Effect on natural ecosystem : eg intestinal flora
AB effect: sensitive vs resistant organism
• Resistance: the inability to kill or inhibit the organism with clinically achievable drug concentrations
• Resistance may be innate (naturally resistant)
• Resistance may be acquired - mutation - acquisition of foreign DNA
• Resistance and MIC
Antimicrobial resistance: contributing factors
• inadequate levels of antibiotics at the site of
infection
• too low dosage of AB
• too short duration of treatment
• overwhelming numbers of organisms
• overuse / misuse of antibiotics
Famous resistant bugs
• MRSA
• VISA/VRSA
• VRE
• ESBL
AB effect: PK/PD
• Pharmacokinetics: what the body does to the drug
• Pharmacodynamics: what the drug does to the body.
GI Absorption
Blood
Renal
excretion
Pharmacokinetics
Extracellular
compartment
of tissues
Oral ingestion
Drug Pharmacokinetics in blood Se
rum
An
tib
ioti
c C
on
cen
trat
ion
0
2
4
6
8
10
0 1 2 3 4 5 6 7 8
Time (hours)
(mcg
/mL)
9 10 11 12
Dose Dose
Effecten anti-infectieus middel: farmakokinetiek- farmacodynamiek
• Relatie antibioticum tot MIC
MIC
conc
tijd
Piekconcentratie/MIC
Duur concentratie boven MIC (time above MIC)
Concentratie-afhankelijke AB
• Piekconc/MIC zo hoog mogelijk: volledige dagdosis in 1 gift (bv. aminoglycosiden)
MIC
conc
tijd
Tijds afhankelijke AB
• ‘time above MIC’ zo lang mogelijk: dagdosis opdelen in frequente giften (bv. betalactam AB)
MIC
conc
tijd
Antibiotic groups
• Beta lactam antibiotics
– Penicillins
– Cephaolsporins
– Carbapenems
– monobactams
• Aminoglycosides
• Macrolides/lincomycins
• Sulfonamides
• Fluoroquinolones
• Glycopeptides
• Tetracyclins
• Oxazolidinones
• Tuberculostatics
• Urinary antiseptics
Classification of antibiotics • Chemical origin
– Natural/semisynthetic/synthetic
• Spectrum of activity – Broad vs narrow spectrum
• Biological activity – Bactericidal/bacteriostatic
• Pharmacodynamic properties – Time vs concentration dependent killing of bacteria
• Mechanism of action
Mechanisms of action
AB that inhibit cell wall synthesis
• Beta lactam antibiotics
– Penicillins
– Cephalosporins
– Carbapenems
– Monobactams
• Glycopeptides
BACTERICIDAL
Small spectrum penicillins
– Beta lactamase (penicillinase) sensitive
• peni V, peni G, benzathinepenicilline
• Good activity to streptococci , no gram neg (only Neisseria), some anaerobic activity (peni G)
• Tonsillitis, pneumonia, meningococcal meningitis
– Beta lactamase (penicillinase) insensitive/antistaphylococcal penicillins
• (Flu)(cl)oxacillin
• Good gram pos activity
• Infections of skin, bone
Broad spectrum penicillins (1)
• Aminopenicillins
– Amoxicillin, ampicillin
• Gram pos (excl S. aur), some gram neg (beta lactamase neg), some anaerobic activity
• Respiratory tract infections (ENT+Lung)
– Amoxicillin + clavulanic acid
• Good gram pos (incl S. aur) and gram neg and anaerobic activity
• Respiratory infections, abdominal infections
Broad spectrum penicillins (2)
• Carboxypenicillins
– Temocillin
– good gram neg activity (excl P. aeruginosa), no gram pos, no anaerobic activity
• Acylureidopenicillins/antipseudomonas pencillins
– Piperacilline+tazobactam
– good gram pos and gram neg (incl P. aeruginosa) and anaerobic activity
– Hospital infections lung, abdomen
Cephalosporins (1)
• 1st generation – Mainly gram pos, some gram neg and anaerobic
• 2nd generation – Weaker gram pos, better gram neg, some anaerob
• 3rd generation – Excellent gram neg, some gram pos and anaerob
• 4th generation – Excellent gram neg, good gram pos, some
anaerob
Cephalosporins (2)
• 1st generation: Cefadroxil, cefazoline
– Tonsillitis, peri-operative prophylaxis
• 2nd generation: Cefaclor, cefuroxime
– Respiratory tract infections
• 3rd generation: Cefotaxim, Ceftriaxone, Ceftazidim
– Sepsis
– Cave only ceftazidim active to P. aeruginosa
• 4th generation: cefepime
– severe hospital infections
carbapenems
• Imipenem, meropenem
• Good gram neg, gram pos and anaerobic activity
• NO: MRSA, MRSE, S. maltophilia, B. cepacia
• Life threatening polymicrobial infections
• CAVE: imipenem and convulsions
• CAVE: carbapenems and secondary yeast infections
monobactams
• Aztreonam
• Good gram neg (also P. aeruginosa), no gram pos,no anaerobic activity
glycopeptides
• Vancomycin, teicoplanin
• good gram pos, some anaerobe activity
• Infections caused by MRSA, ampi R enterococcen, methi R CNS
• Cave red man syndrome
Mechanisms of action
Inhibition of protein synthesis
• Macrolides, lincosamides
• Aminoglycosides
• Tetracyclins
• Fluoroquinolones
BACTERIOSTATIC (ML,LC)
BACTERICIDAL (AG, TC, FQ)
macrolides
• Azithromycin, clarithromycin, erythromycin, roxithromycin
• Gram pos and atypical organisms ( Mycoplasma
Chlamydia, Legionella), some gram neg and anaerobic activity
• Respiratory infections caused by atypical organisms and B. pertussis
lincomycins
• clindamycin
• Gram pos and anaerobic activity
• Bone infections
• CAVE: pseudomembranous colitis
aminoglycosides
• Amikacin, gentamycin, tobramycin
• Excellent gram neg, some gram pos (no streptococci), Mycobacteria
• Severe hospital infections: sepsis, endocarditis, pyelonephritis, pneumonia
• Synergistic action with beta lactam AB
• CAVE never monotherapy!
• Toxicity:
– Kidney: reversible
– Middle ear: irreversible
• ODD: less nefrotoxicity
fluoroquinolones
• Ciprofloxacin, (levofloxacin, norfloxacin, ofloxacin)
• Good gram neg and atypical, some gram pos and anaerobic activity
• Cystic fibrosis, urinary tract infection caused by P. aeruginosa
• Toxic effect on cartilago: not confirmed in human studies
Mechanisms of action
Inhibition of metabolic pathways
• Trimethoprim/Sulfomethoxazole
• Inhibition of folic acid synthesis
• Bacteriostatic, combination bactericidal
• gram neg and gram pos activity
• Urinary tract infections, Pneumocystis jiroveci, respiratory infections
sulfonamides
• Bacteriostatic/ combination bactericidal
• Inhibition of bacterial folic acid synthesis
Most appropriate AB therapy: THE CHOICE
• Micro-organisms must be sensitive
• AB must be able to reach site of infection
– PK/PD dynamics
• MIC/MBC
• Time dependent vs concentration dependent killing
• Minimal side effects
• Minimising risk of development of resistance
How to avoid/overcome AB resistance
• AB:
–Alter structure of AB (cephalosporins) –Add beta lactamase inhitor
• High dosage of AB “dead bugs dot not mutate”
• Restrictive use of AB –Guidelines – Switch to smaller spectrum AB according to
microbiological results • Hygienic measures to avoid transfer of
organisms
Bactericidal vs bacteriostatic
Beta lactamases
• Production of beta lactamase most important resistance mechanism to beta lactam antibiotics
• Beta lactamase production in both gram negative (e.g. E. coli, K. pneumoniae, P. mirabilis) and gram positive bacteria (S. aureus, B. fragilis)
• Can be overcome by addition of beta lactamase inhibitor to antibiotic (e.g. clavulanic acid, tazobactam)
What additional bugs do they cover?
• S. aureus
• H. influenzae
• Neisseria sp.
• Bacteroides fragilis
• E. coli and Klebsiella
• Not better for Pseudomonas or Enterobacter